Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

• Published in: Nature communications Vol. 9; no. 1; pp. 2032 - 12
• Main Authors: Garcia-Lopez, Amparo, Tessaro, Francesca, Jonker, Hendrik R. A., Wacker, Anna, Richter, Christian, Comte, Arnaud, Berntenis, Nikolaos, Schmucki, Roland, Hatje, Klas, Petermann, Olivier, Chiriano, Gianpaolo, Perozzo, Remo, Sciarra, Daniel, Konieczny, Piotr, Faustino, Ignacio, Fournet, Guy, Orozco, Modesto, Artero, Ruben, Metzger, Friedrich, Ebeling, Martin, Goekjian, Peter, Joseph, Benoît, Schwalbe, Harald, Scapozza, Leonardo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.05.2018; Nature Publishing Group; Macmillan; Nature Portfolio
• Subjects: 101/6; 13; 14; 38; 38/77; 38/91; 49; 631/154/1435/2163; 631/154/556; 631/45/500; 631/45/535/1267; 631/45/535/878/1263; Alternative Splicing; Animals; Animals, Genetically Modified; Atrophy; Atròfia muscular; Chemical Sciences; Cribratge; Drosophila; Drug discovery; Drug Evaluation, Preclinical; Exons - genetics; HeLa Cells; Humanities and Social Sciences; Humans; Imidazoles - chemistry; Imidazoles - pharmacology; Imidazoles - therapeutic use; Indoles - chemistry; Indoles - pharmacology; Indoles - therapeutic use; Infant mortality; Medical screening; Molecular chains; Molecular modelling; Molecular Targeted Therapy - methods; multidisciplinary; Muscular atrophy; Muscular Atrophy, Spinal - drug therapy; Muscular Atrophy, Spinal - genetics; Mutation; Neuromuscular diseases; NMR; Nuclear magnetic resonance; Organic chemistry; Pharmaceuticals; Phenotype; Phenotypes; Proteins; R&D; Regulatory Elements, Transcriptional - drug effects; Research & development; Ribonucleic acid; RNA; RNA Splice Sites; RNA, Messenger - chemistry; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); SMN protein; Spectrum analysis; Spinal muscular atrophy; Splicing; Survival of Motor Neuron 2 Protein - genetics; Target recognition

Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, w...